Signal transduction pathways activated by RET oncoproteins in PC12 pheochromocytoma cells.
Gene alterations in the ret proto-oncogene, which encodes a receptor tyrosine kinase, have been found to associate with several human diseases. In this study, we showed that induction of the vgf promoter activity is a good molecular indicator for RET activation in PC12 cells, a rat pheochromocytoma cell line. We demonstrated that all forms of RET oncoprotein, including RET chimeric oncoproteins found in human papillary thyroid carcinomas (RET/PTC) as well as RET oncoproteins found in patients with multiple endocrine neoplasia type 2A and 2B (2A/RET and 2B/RET) can induce vgf promoter activity in PC12 cells. In contrast, a RET mutant found in a patient with Hirschsprung's disease, as well as a RET/PTC1 mutant with deletion of the dimerization domain, failed to induce vgf promoter activity in PC12 cells. We further determined that the signaling events mediated by phosphorylated Tyr294 and phosphorylated Tyr451 binding sites are essential for RET/PTC1 to induce vgf promoter activity in PC12 cells. We also showed that RET/PTC1, 2A/RET, and 2B/RET induce ELK-, cAMP-responsive element binding protein (CREB), or JUN-mediated gene expression in PC12 cells, and these three signaling events are mediated by phosphorylated Tyr294 and phosphorylated Tyr451 binding sites in RET/PTC1.
Xing
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Department of Physiology, The Ohio State University, Columbus, Ohio 43210, USA.
Furminger
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Tong
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Jhiang
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SM
D000818:Animals; D001665:Binding Sites; D002291:Carcinoma, Papillary / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D029721:Drosophila Proteins; D015972:Gene Expression Regulation, Neoplastic; D006627:Hirschsprung Disease / Q000235:genetics; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009479:Neuropeptides; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D009479:Neuropeptides; D011506:Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; C062040:Vgf protein, rat; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4; D036081:Receptors, Eph Family; C416649:Ret protein, Drosophila; C495001:Ret protein, rat